tbuckley/cabot-search huggingface dataset:
Abstract 2135: Targeting N-Myc in neuroblastoma cells with selective Aurora kinase A degraders
Authors: Jian Tang, Ramkumar Moorthy, Ozlem Demir, Zachary D. Baker, Jordan A. Naumann, Katherine F. Jones, Michael J. Grillo, Ella Haefner, Ke Shi, Michaella J. Levy, Hideki Aihara, Reuben S. Harris, Rommie E. Amaro, Nicholas M. Levinson, Daniel A. Harki
Journal: Cancer Research (2022)

Abstract Overexpression of the MYCN proto-oncogene is one of the strongest biomarkers for poor prognosis in neuroblastoma patients. N-Myc, encoded by MYCN, is a highly attractive yet “undruggable” target in neuroblastoma drug discovery. N-Myc is a short-lived protein in normal neuronal progenitor cells; however, in MYCN-amplified neuroblastoma cells, overexpressed N-Myc is stabilized by high levels of Aurora kinase A (Aurora-A). Several Aurora-A allosteric modulators have been developed to disassociate N-Myc binding and promote its degradation. These compounds function through a competitive mechanism against N-Myc, and clinical trial results suggest limited efficacy in high-risk neuroblastoma patients where N-Myc is highly expressed. To develop Aurora-A modulators with greater effects in destabilizing N-Myc, targeted degradation of Aurora-A was investigated in this study. First, we developed a highly selective Aurora-A-binding ligand by chemically modifying ribociclib, which targets CDK4/6. Next, a series of potent Aurora-A/N-Myc degraders were developed using proteolysis targeting chimaera (PROTAC) technology. Our lead compound, HLB-0532259, was found to substantially decrease N-Myc levels in neuroblastoma cells following the degradation of Aurora-A with nanomolar potency. Mechanistic studies suggest that HLB-0532259 binds to Aurora-A in an uncompetitive manner with respect to N-Myc, which contributes to its high potency for degrading the Aurora-A/N-Myc pool. Mass spectrometry analysis demonstrates that HLB-0532259 possesses remarkable proteome-wide selectivity for Aurora-A and N-Myc degradation. Further studies have revealed that HLB-0532259 exhibits nanomolar cytotoxicities against a panel of MYCN-amplified neuroblastoma cells, good pharmacokinetic properties, and favorable therapeutic outcomes in a xenograft neuroblastoma mouse model. Taken together, our data strongly support HLB-0532259 as a promising lead compound for neuroblastoma therapy. Citation Format: Jian Tang, Ramkumar Moorthy, Ozlem Demir, Zachary D. Baker, Jordan A. Naumann, Katherine F. Jones, Michael J. Grillo, Ella Haefner, Ke Shi, Michaella J. Levy, Hideki Aihara, Reuben S. Harris, Rommie E. Amaro, Nicholas M. Levinson, Daniel A. Harki. Targeting N-Myc in neuroblastoma cells with selective Aurora kinase A degraders [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2135.
Treatment of Anal High-Grade Squamous Intraepithelial Lesions to Prevent Anal Cancer
Authors: Joel M. Palefsky, Jeannette Y. Lee, Naomi Jay, Stephen E. Goldstone, Teresa M. Darragh, Hillary A. Dunlevy, Isabella Rosa-Cunha, Abigail Arons, Julia C. Pugliese, Don Vena, Joseph A. Sparano, Timothy J. Wilkin, Gary Bucher, Elizabeth A. Stier, Maribel Tirado Gomez, Lisa Flowers, Luis F. Barroso, Ronald T. Mitsuyasu, Shelly Y. Lensing, Jeffrey Logan, David M. Aboulafia, Jeffrey T. Schouten, Juan de la Ossa, Rebecca Levine, Jessica D. Korman, Michael Hagensee, Thomas M. Atkinson, Mark H. Einstein, Bernadette M. Cracchiolo, Dorothy Wiley, Grant B. Ellsworth, Cristina Brickman, J. Michael Berry-Lawhorn
Journal: New England Journal of Medicine (2022)

The incidence of anal cancer is substantially higher among persons living with the human immunodeficiency virus (HIV) than in the general population. Similar to cervical cancer, anal cancer is preceded by high-grade squamous intraepithelial lesions (HSILs). Treatment for cervical HSIL reduces progression to cervical cancer; however, data from prospective studies of treatment for anal HSIL to prevent anal cancer are lacking.
Abstract 5622: Preclinical evaluation of humanized PD1/GITR combination therapy using double humanized mouse
Authors: Dongdong Yuan, Dongdong zhang, Hongyan Sun, Mingkun Zhang, Liyou Dong, Cunxiang Ju, Shuai Li, Huiyi Wang, Jing Zhao, Xiang Gao
Journal: Cancer Research (2022)

Abstract GITR (glucocorticoid-induced TNFR-related protein) is a member of tumor necrosis factor receptor superfamily, expressed on many kinds of cells including T cells, attracting attention as a co-stimulatory immune checkpoint molecule. GITRL, the ligand of GITR is mainly expressed on antigen presenting cells. GITR/GITRL interaction plays an important role on the development of immune response, which can serve as promising anti-tumor target. While more than twenty anti-GITR antibodies are at clinical stages, combination treatments of GITR agonist and PD-1 inhibitor may be a better choice. Thus, there is a need for pre-clinical mouse model to evaluate the anti-tumor effect of humanized PD1/GITR antibodies. Gempharmatech established PD1/GITR double humanized mouse line on a BALB/c background, in which the extracellular domain of mGITR was replaced with its human counterparts while the trans-membrane and cytoplasmic domain kept intact, as well as the same strategy of PD1. BALB/c-hPD1/hGITR mouse could successfully express similar levels of hGITR and hPD1 compared with BALB/c wild type mice. Moreover, no immune or developmental abnormalities were observed in the humanized mouse. Anti-GITR combination with anti-PD1 presented greater tumor growth inhibition than anti-PD1 or anti-GITR monotherapies in PD1/GITR double humanized mouse bearing CT26 tumors. In summary, BALB/c-hPD1/hGITR are valuable models for the pre-cilincal evaluation of candidate humanized PD1/GITR combination treatment or bispecific antibody therapies. Citation Format: Dongdong Yuan, Dongdong zhang, Hongyan Sun, Mingkun Zhang, Liyou Dong, Cunxiang Ju, Shuai Li, Huiyi Wang, Jing Zhao, Xiang Gao. Preclinical evaluation of humanized PD1/GITR combination therapy using double humanized mouse [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5622.
Abstract 5652: A novel anti apoptotic function of CTLA4 in melanoma
Authors: Hasan Raza Kazmi, Xuan Mo, Bo Zhou, Sara Preston-Alp, Scott Gross, Hassaan Wajeeh, Carmen Merali, Jonathan Soboloff, Salim Merali, M. Raza Zaidi
Journal: Cancer Research (2022)

Abstract Cytotoxic T Lymphocyte Antigen 4 (CTLA4) is an important immune checkpoint protein and has been utilized as an immunotherapeutic target against melanoma. Our previous studies have shown that CTLA4 is expressed at low levels in primary human melanocytes but is upregulated in mutant-BRAF/NRAS melanoma cells and tissues. Despite predominantly intracellular localization of CTLA4, its intracellular function remains highly contradictory and unsubstantiated. We found that ectopic expression of Ctla4 in mouse melanoma cell lines substantially promoted lung colonization in allograft model systems in syngeneic mice. Moreover, similar results were observed in immunocompromised recipient mice, suggesting an intracellular cell-autonomous tumorigenic role of Ctla4 in melanoma. These finding led us to investigated intracellular functions of CTLA4 and its potential roles in melanomagenesis. Through the Ingenuity Pathway Analysis of our proteomics data, we found apoptosis as a major affected pathway in Ctla4-expressing mouse melanoma cells. We treated the cells (B2905-Ctla4-ee and EV control) with doxorubicin to induce apoptosis, followed by assessment by Annexin V assay. We found that Ctla4 expressing mouse melanoma cells were significantly resistant to doxorubicin-induced apoptosis. In reciprocal experiment, we generated (by CRISPR-Cas9) CTLA4-knockout A2058 human melanoma cells that exhibit high endogenous CTLA4 expression and we found that knockout cells showed significantly increased apoptosis than the parental cells. Moreover, we also observed significant upregulation of anti-apoptotic proteins (Bnip3, Birc6, Pak1, Mcl-1, Survivin, Rac1/Cdc42, Bcl-2, and Bnip3l) and downregulation of pro-apoptotic proteins (p53 and Bad) in CTLA4-expressing human melanoma cell lines. CTLA4-expressing cells also showed significantly higher invasion in Matrigel-coated transwell assay. These findings lead us to conclude that CTLA4 plays a significant role in regulating apoptosis and promoting melanoma progression in BRAF/NRAS mutant cells. Citation Format: Hasan Raza Kazmi, Xuan Mo, Bo Zhou, Sara Preston-Alp, Scott Gross, Hassaan Wajeeh, Carmen Merali, Jonathan Soboloff, Salim Merali, M. Raza Zaidi. A novel anti apoptotic function of CTLA4 in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5652.
Abstract 2395: Homozygous <i>MTAP</i> deletion in primary human glioblastoma is not associated with elevation of methylthioadenosine
Authors: Yasaman Barekatain, Jeffrey Ackroyd, Victoria Yan, Sunada Khadka, Ko-Chien Chen, Raghu Kalluri, John de Groot, Jason Huse, Florian muller
Journal: Cancer Research (2022)

Abstract Homozygous deletion of the CDK2NA locus frequently results in the co-deletion of methylthioadenosine phosphorylase (MTAP) in many fatal cancers such as glioblastoma multiform (GBM). In cell culture, cell lines with MTAP-deletions show elevations of its substrate metabolite, methylthioadenosine (MTA). High levels of MTA inhibit PRMT5, which sensitizes MTAP-deleted cell lines to PRMT5 and MAT2A inhibition. While extensively corroborated in vitro, the clinical efficacy of these strategies ultimately relies on equally significant accumulations of MTA in human tumors. In this work, using comprehensive metabolomic profiling, we show that MTA is primarily secreted, resulting in exceedingly high levels of extracellular MTA in vitro. We further show that primary human glioblastoma tumors minimally accumulate MTA in vivo, which is likely explained by the metabolism of MTA by MTAP-competent stromal cells. Together, these findings highlight the metabolic discrepancies between in vitro models and primary human tumors and should thus be carefully considered in the development of the precision therapies targeting MTAPhomozygous deleted GBM. Citation Format: Yasaman Barekatain, Jeffrey Ackroyd, Victoria Yan, Sunada Khadka, Ko-Chien Chen, Raghu Kalluri, John de Groot, Jason Huse, Florian muller. Homozygous MTAP deletion in primary human glioblastoma is not associated with elevation of methylthioadenosine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2395.
Abstract 3553: Harnessing soluble CD40L to enhance anti-tumor efficacy of Her2-LAMP DNA vaccine using UNITE࣪ platform
Authors: Wei Shen, Renhuan Xu, Yun-Ting Kao, Mohan Karkada, Teri Heiland
Journal: Cancer Research (2022)

Abstract CD40 ligand (CD40L; CD154) is a transmembrane protein expressed on the surface of activated T cells, particularly on CD4 T cells, that stimulates CD40-dependent activation of antigen-presenting cells, resulting in enhancement of T cell and antibody responses. Soluble multimeric forms of CD40L (sCD40L) act as an effective adjuvant to enhance vaccine immunogenicity. We previously developed a Her2/Neu-LAMP DNA vaccine based on our proprietary UNITE࣪ (UNiversal Intracellular Targeted Expression) platform, which fuses a tumor-associated antigen with lysosomal associated membrane protein 1 (LAMP-1). To increase T cell responses induced by this vaccine, we developed a bicistronic DNA construct in which both the tumor antigen (Her2) fused with LAMP and sCD40L were expressed separately. Secretion of CD40L was confirmed by transient transfection of 293T cells with plasmid DNA followed by ELISA for sCD40L in the cell culture supernatant. Intradermal vaccination of mice with bicistronic Her2-LAMP-sCD40L elicited significantly enhanced Her2-specific T cell and antibody responses compared with mice immunized with Her2-LAMP DNA. Intracellular staining revealed that inclusion of sCD40L in the vaccine induced potent antigen specific T cell IFNγ production, primarily in CD4 T cells. Furthermore, in a murine TSA breast cancer model, Her2-LAMP-sCD40L significantly inhibited tumor growth and prolonged survival in a therapeutic vaccine setting, suggesting that this novel bicistronic vaccine is an effective strategy to promote anti-tumor efficacy in vivo. Ongoing studies are aimed at exploring vaccine-induced changes within the tumor microenvironment, including cytokine profiles, expression of PD-1/PD-L1, and effect on myeloid derived suppressor cells and NK cells. This new approach in bicistronic DNA vaccine design using the UNITE࣪ platform may provide future therapeutic benefit for multiple Her2-expressing cancer types. Citation Format: Wei Shen, Renhuan Xu, Yun-Ting Kao, Mohan Karkada, Teri Heiland. Harnessing soluble CD40L to enhance anti-tumor efficacy of Her2-LAMP DNA vaccine using UNITE࣪ platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3553.
Abstract 1830: Phenylacetaldehyde induces apoptosis through endoplasmic reticulum and potentiates the effect of 5-FU treatment in colorectal cancer cells
Authors: Sylvain Ferrandon, Cheng Kong, Joseph Fedro, Rami-James Aoun, Chureeporn Chitchumroonchokchai, Steven Clinton, Matthew F. Kalady
Journal: Cancer Research (2022)

Abstract Introduction: Phenylacetaldehyde (PAA), a product of phenylalanine metabolism, is generated by microbiota and has demonstrated anticancer properties in breast cancer. As the gut microbiome influences intestinal homeostasis, we investigated the effects of PAA on colorectal cancer (CRC). Methods: Serum PAA levels and feces microbiota from 30 CRC patients and 30 healthy controls were analyzed by targeted GC-MS/MS and metagenomic sequencing. A validation cohort of 75 CRC patients and 53 healthy controls was analyzed for PAA level in serum. CRC cell lines and CRC-patient derived organoids were cultured and treated with PAA alone and in combination with 5-fluouracil (5-FU, standard chemotherapy used for CRC), then evaluated for viability, proliferation, cell cycle distribution, and cell death in vitro. We interrogated the mechanistic pathways induced by PAA treatment using RNA sequencing and western blot. Results: PAA levels were significantly decreased in the circulation of CRC patients compared to healthy controls in our study population and the validation cohort. Metagenomic sequencing indicated the bacteria that positively correlated with PAA levels were significantly more abundant in healthy controls; while bacteria that negatively correlated with PAA were more abundant in CRC. In vitro, PAA inhibited the viability and colony formation of CRC cell lines as well as human-derived organoids in a concentration-dependent manner. Mechanistically, PAA treatment induced a P53-dependant G1 cell cycle arrest and cell death in HCT116 and RKO cell lines. Proteomic analysis also demonstrated a downregulation in PI3K/AKT/mTOR and ERK pathways. Investigation by RNA sequencing showed that PAA inhibits CRC by inducing endoplasmic reticulum stress-induced autophagy. When combined with 5-FU, PAA enhanced the potency of 5-FU on viability, cell death, and cell cycle arrest by inducing DNA damage. Conclusions:The bacteria metabolite PAA increased CRC cell death by endoplasmic reticulum stress-induced autophagy and downregulation of the PI3K/AKT/mTOR and ERK pathways. PAA also potentiated chemotherapeutic efficacy of 5-FU through induction of DNA damages. These findings warrant further exploration of PAA as a potential CRC biomarker and novel therapeutic agent. Citation Format: Sylvain Ferrandon, Cheng Kong, Joseph Fedro, Rami-James Aoun, Chureeporn Chitchumroonchokchai, Steven Clinton, Matthew F. Kalady. Phenylacetaldehyde induces apoptosis through endoplasmic reticulum and potentiates the effect of 5-FU treatment in colorectal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1830.
Abstract 6122: Different characteristics of tumor immune microenvironment between LUSC and LUAD
Authors: Na Li, Mengna Hu, Ding Zhang, Xiaoyu Ji
Journal: Cancer Research (2022)

Abstract Background: Patients with lung squamous cell carcinoma (LUSC) have higher tumor mutation burden (TMB) and PD-L1 expression than those with lung adenocarcinoma (LUAD). Several studies showed that tumor immune microenvironment (TIME), mainly the tumor-infiltrating immune cells, may affect the efficacy of immunotherapy. However, the comparison of tumor immune microenvironment between LUAD and LUSC is little known. Methods: 14 patients with LUSC and 21 patients with LUAD were enrolled in the retrospective analysis of multiple immunofluorescence staining to assess the number of immune cells. Genomic profiling of DNA was performed on formalin-fixed paraffin-embedded tumor samples from 3752 LUAD and 459 LUSC patients by NGS with 733 cancer-related genes panel. TMB is defined as the total counts of single nucleotide variants and indels in the exon region. Results: Overall, as the most abundant tumor-infiltrating immune cells in both groups, CD3+ cells are more in LUAD [median (number/mm2 in LUSC vs in LUAD): 312 vs 918, p = 0.02]. However, there were no significant differences in CD8+ T cells (median: 48 vs 36, p = 0.74), indicating higher infiltration of T lymphocytes rather than cytotoxic T lymphocytes (CTLs) in LUAD than that in LUSC. Unlike in tumor, LUAD patients had both more T lymphocytes (p &amp;lt; 0.001) and CTLs (p &amp;lt; 0.01) in stroma. Besides, LUSC was correlated with fewer M2 tumor-associated macrophages (TAMs) and PD-1+ immune cells (p &amp;lt; 0.001; p = 0.02), while no significant differences were found in tumor-infiltrating FOXP3+ cells (p = 0.41) and B lymphocytes (p = 0.61). In addition, natural killer cells were the fewest among the tumor-infiltrating lymphocytes detected in both groups (median: 2 vs 13). Similar to the previous studies, TMB level was higher in LUSC (median: 8.94 vs 3.36, p &amp;lt; 0.0001). Although LUSC patients had a larger proportion of positive PD-L1 expression (45% vs 30.5%, p &amp;lt; 0.0001) and strong PD-L1 expression in tumor cells (20.9% vs 10.7%, p &amp;lt; 0.0001), the number of CTLs and TAMs expressing PD-L1 is significantly lower than that in LUAD ( p = 0.04; p = 0.0001). Conclusion: LUAD had more immune invasion, while LUSC was related to higher TMB and PD-L1 expression. It suggested that the mechanisms affecting the benefits of immunotherapy may be different. The immune microenvironment of tumor and stroma should be considered simultaneously to explore the mechanism of immunotherapy and the respective thresholds should be selected according to the types of immune cells. Citation Format: Na Li, Mengna Hu, Ding Zhang, Xiaoyu Ji. Different characteristics of tumor immune microenvironment between LUSC and LUAD [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6122.
Abstract 3060: Changes in mouse gut microbiome upon exposure to N-butyl-N-(4-hydroxybutyl) nitrosamine
Authors: Rashida Ginwala, Laura Bukavina, Jodie Franklin, Mohit Sindhani, Philip Abbosh
Journal: Cancer Research (2022)

Abstract Background: BBN (N-butyl-N-(4-hydroxybuytl) nitrosamine), a closely related compound to the carcinogens found in tobacco smoke is an attractive and most commonly used agent to model bladder cancer in mice. BBN closely recapitulates the morphological characteristics of human bladder cancer and conceptually simulates tobacco exposure as the leading risk factor for bladder cancer. We employ the BBN model in mice to decipher the microbial changes that occur in the gut of the mice during the chemical carcinogenesis induced by BBN exposure. Methods: Starting at 8-12 weeks of age, male (N=30) and female (N=21) C57BL/6 mice were administered 0.05% BBN in drinking water for 12 weeks then switched to regular water. Control mice drank regular water. Stool was collected pre-exposure, after 6 and 12 weeks of exposure, and at the time of tumor identification (tumors typically detectable between 14-22 weeks from start of treatment using this model). DNA extracted from stool was subjected to PCR amplification using primers for the V3-V4 regions of the bacterial 16S rRNA. Results: Gender-based differences in the microbial composition were noted in response to BBN treatment. While gut microbial diversity in the female mice was markedly reduced (Shannon, Simpson, Inverse Simpson, and Richness) upon BBN treatment, that of male mice remained unchanged from baseline. Additionally, there was a distinct clustering of microbes based on sex (p=0.024) but not BBN exposure (p=0.86) as evidenced by principal coordinate analysis. Differences in the microbial composition were seen upon BBN exposure, with BBN mice showing an increase in Bacteroidales (53%), Lactobacillales (17.5%), Coriobacteriales (19.87%) in females and male mice exhibited an increase in Erysipelotrichales (14.76%) at the order level. On the other hand while male mice showed no significant decreases, female mice exhibited reduction in abundance of Clostridiales (log change -7.79, padj &amp;lt;0.004), Veeruccomicrobiales (log change -2.21, padj&amp;lt;0.005), and Bacillales (log -17.60, padj =0.005). Conclusions: Pronounced gut microbial changes are induced by BBN in the murine model, with microbiome of the female mice exhibiting more significant variations compared to baseline, suggesting gender-based disparities in the effect of BBN exposure. Citation Format: Rashida Ginwala, Laura Bukavina, Jodie Franklin, Mohit Sindhani, Philip Abbosh. Changes in mouse gut microbiome upon exposure to N-butyl-N-(4-hydroxybutyl) nitrosamine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3060.
Abstract 5677: βTrCP1 is a substrate of extracellular signal-regulated kinase 2
Authors: Ga-Eun Lee, Cheol-Jung Lee, Hyun-Jung An, Weidong Chen, Dohyun Jeung, Youngwon Choi, Yong-Yeon Cho
Journal: Cancer Research (2022)

Abstract ERK1 and ERK2, downstream kinases of MEKs, transduce activation signals to a large number of cytosolic and nuclear substrates specifically involved in cellular signaling of transcription factors responsible for particular cellular processes. Thus, dysregulation of the cascade frequently leads to the development of diverse diseases, including &amp;gt; 90% of all cancers. However, although signaling mechanisms of ERKs by phosphorylation have well-known, long-term protein amount regulation has not clearly elucidated. In this study, we proved that βTrCP1 is a novel binding protein of ERK2. The interaction between ERK2 and βTrCP1 was occurred via F-box and linker domains spanning aa 192-265. Amino acid alignment of βTrCP1 showed that there are two independent putative sites for ERK docking. The mutations of the putative docking sites from lysine to alanine abrogated the interaction between ERK2 and βTrCP1. Importantly, ERK activation induced by epidermal growth factor induces βTrCP1 phosphorylation, resulting in facilitation of βTrCP1 half-life. Although the phosphorylation sites of βTrCP1 by ERK2 has not been identified, βTrCP1 tumor suppressive activity may be regulated via ERK2 when the cells are stimulated by tumor promoters such as EGF. Citation Format: Ga-Eun Lee, Cheol-Jung Lee, Hyun-Jung An, Weidong Chen, Dohyun Jeung, Youngwon Choi, Yong-Yeon Cho. βTrCP1 is a substrate of extracellular signal-regulated kinase 2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5677.